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Open AccessArticle

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

1
Department of Physiology and Pharmacology, Federal University of Santa Maria, Santa Maria 97105900, Rio Grande do Sul, Brazil
2
Neonatal Research Group, Health Research Institute La Fe, 46026 Valencia, Spain
3
Department of Physiology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Valencia, Spain
4
Department of Morphology, Federal University of Santa Maria, Santa Maria 97105900, Rio Grande do Sul, Brazil
*
Authors to whom correspondence should be addressed.
Isabela A. Finamor and Caroline A. Bressan are equal first authors.
Biology 2021, 10(2), 82; https://doi.org/10.3390/biology10020082
Received: 23 December 2020 / Revised: 19 January 2021 / Accepted: 20 January 2021 / Published: 22 January 2021
Aspartame is an artificial sweetener used in foods and beverages worldwide to prevent increasing obesity and diabetes mellitus, acting as a tool to help the control of caloric intake. However, its chronic intake is controversial since it has been linked to some adverse effects including oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. Thus, this work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Aspartame generated liver injury and fibrosis. It also decreased the activity of antioxidant enzymes and increased the levels of lipid peroxidation, thus, probably, triggering inflammation and cell death through the induction of protein 53 (p53). Finally, via p53 activation, aspartame inhibited a transcriptional coactivator, the peroxisome proliferator-activated receptor gamma coactivator 1 alpha, a master regulator of glucose and lipid metabolism, probably leading to changes in lipid profile in serum, total lipid accumulation, as well as an impairment in the gluconeogenesis in mouse liver, thus causing hypoglycemia. Therefore, this study provides new insights to understand the mechanisms related to aspartame-linked adverse effects, showing that its intake should be cautioned.
Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue. View Full-Text
Keywords: aspartame; liver fibrosis; lipid peroxidation; Nrf2; inflammasome; PGC-1α; lipid; hypoglycemia; gluconeogenesis aspartame; liver fibrosis; lipid peroxidation; Nrf2; inflammasome; PGC-1α; lipid; hypoglycemia; gluconeogenesis
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MDPI and ACS Style

Finamor, I.A.; Bressan, C.A.; Torres-Cuevas, I.; Rius-Pérez, S.; da Veiga, M.; Rocha, M.I.; Pavanato, M.A.; Pérez, S. Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice. Biology 2021, 10, 82. https://doi.org/10.3390/biology10020082

AMA Style

Finamor IA, Bressan CA, Torres-Cuevas I, Rius-Pérez S, da Veiga M, Rocha MI, Pavanato MA, Pérez S. Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice. Biology. 2021; 10(2):82. https://doi.org/10.3390/biology10020082

Chicago/Turabian Style

Finamor, Isabela A.; Bressan, Caroline A.; Torres-Cuevas, Isabel; Rius-Pérez, Sergio; da Veiga, Marcelo; Rocha, Maria I.; Pavanato, Maria A.; Pérez, Salvador. 2021. "Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice" Biology 10, no. 2: 82. https://doi.org/10.3390/biology10020082

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